Abstract Simultaneous measurement of gastric pH and the gastric mucosa potential difference (GPD) before and after treatment was performed to evaluate the effect of S-carboxymethylcysteine lysine salt (SCMC-Lys) and N-acetylcysteine (NAC) on the integrity of the gastric mucosal barrier. Six dyspeptic patients were treated in a double-blind, double-dummy, crossover study. The drugs were administered orally in a single dose of 2.7 g granulated SCMC-Lys (daily therapeutic dose) and a single dose of 200 mg NAC (the therapeutic dosage of NAC is 200 mg BID or TID). The pH values before and after treatments were normal. SCMC-Lys induced a less pronounced change in GPD parameters than NAC: the time during which GPD values were below base-line values was shorter after SCMC-Lys treatment (mean, 70.8 min ± 39.6) than after NAC treatment (mean, 82.0 min ± 34.7); the maximum change of GPD was significantly lower after SCMC-Lys treatment (mean, 17.16 mV ± 4.7) than after NAC treatment (mean, 24.0 mV ± 6.2; P < 0.001, Student's t test); and the Reiz index, a predictive index of mucosal damage, was lower after SCMC-Lys treatment (mean, 20.77 ± 27.78) than after NAC treatment (mean, 31.85 ± 27.09). The results show that NAC induced changes on the gastric mucosal barrier as evaluated by GPD, whereas SCMC-Lys did not.